TTF1-associated pneumopathy

Thyroid transcription factor-1 (TTF-1) deficiency syndrome is characterized by neurologic, thyroidal and pulmonary dysfunction.

Children usually have mild-to-severe respiratory symptoms and occasionally die of respiratory failure.

Synopsis

 respiratory insufficiency
 mild hyaline membrane disease
 continuous ventilatory support
 symmetrically distributed pulmonary cysts by imaging.
 pneumonia
 respiratory failure

Pathology

 visible emphysematous changes
 "cysts" up to 2 mm in diameter.
 The airway generations and radial alveolar count were diminished.
 Acute bacterial pneumonia, alveolar septal fibrosis, pneumocyte hypertrophy and clusters of airspace macrophages can be focally present.
 Abnormal airway and alveolar morphogenesis
 Altered expression of surfactant-associated proteins, which may explain the respiratory difficulties encountered in TTF-1 haploinsufficiency.

Physiopathology

 TTF-1 plays an important role in pulmonary morphogenesis and surfactant metabolism.

Ultrastructure

 Type II pneumocytes have numerous lamellar bodies.
 Alveolar spaces contain fragments of type II pneumocytes and extruded lamellar bodies.

Immunochemistry

 Immunoreactivity for surfactant protein SP-A and ABCA3 is diminished.
 Immunoreactivity for SP-B and proSP-C is robust, although irregularly distributed, corresponding to the distribution of type II pneumocytes.
 Immunoreactivity for TTF-1 protein is readily detected.

Etiology

 constitutional 14q12-21.3 haploid deletion encompassing the TTF-1

• cerebral dysgenesis
• thyroidal dysfunction

References

 A novel presentation of diffuse lung disease caused by congenital hypothyroidism. Shenoy A, Esquibies AE, Dunbar N, Dishop MK, Reyes-Mugica M, Langston C, Deladoëy J, Abu-Khudir R, Carpenter T, Bazzy-Asaad A. J Pediatr. 2009 Oct;155(4):593-5. PMID: 19773006

 Pulmonary Pathology in Thyroid Transcription Factor-1 Deficiency Syndrome. Galambos C, Levy H, Cannon CL, Vargas SO, Reid LM, Cleveland R, Lindeman R, Demello DE, Wert SE, Whitsett JA, Perez-Atayde AR, Kozakewich H. Am J Respir Crit Care Med. 2010 Mar 4. PMID: 20203240

 A novel presentation of diffuse lung disease caused by congenital hypothyroidism. Shenoy A, Esquibies AE, Dunbar N, Dishop MK, Reyes-Mugica M, Langston C, Deladoëy J, Abu-Khudir R, Carpenter T, Bazzy-Asaad A. J Pediatr. 2009 Oct;155(4):593-5. PMID: 19773006

 Lethal respiratory failure and mild primary hypothyroidism in a term girl with a de novo heterozygous mutation in the TITF1/NKX2.1 gene. Maquet E, Costagliola S, Parma J, Christophe-Hobertus C, Oligny LL, Fournet JC, Robitaille Y, Vuissoz JM, Payot A, Laberge S, Vassart G, Van Vliet G, Deladoëy J. J Clin Endocrinol Metab. 2009 Jan;94(1):197-203. Epub 2008 Oct 28. PMID: 18957494 [Free]